FORD, SHAVON L., M.S. Synthetic and Molecular Modeling Studies of Antiangiogenic Compounds Based on Solenopsin A Lead Structure. (2009) Directed by Dr. Phillip J. Bowen. 41 pp.
The imported fire ants, Solenopsis invicta, were introduced into the United States
by way of Alabama in the mid 1930s. Their devastating impact on the agriculture of the
south led to a project to eradicate them, which in turn resulted in the discovery of the
antiangiogenic activity of a component of their venom. The discovery of 2-methyl-6-
alkyl piperidines has led to the synthesis and study of solenopsin A, a trans-2-methyl-6-
n-undecyl piperidine and analogs. Solenopsin A has proven effective in biological
testing of zebrafish for antiangiogenic studies, thus qualifying it and its analogs as viable
candidates for further studies.
Angiogenesis, a term coined by P. Shubik in 1968, is the growth of blood vessels
from previously existing vessels. Angiogenesis is a normal physiological process in
humans during early childhood development, but seldom in adults. The dominant disease
that is affected by angiogenesis is cancer, which progresses through tumor growth.
Angiogenesis inhibition, also termed antiangiogenesis, appears to have a very exciting
future in cancer therapy. Antiangiogenic molecules have been prepared and studied as
potential new therapeutics, and they should be advantageous over the commonly used
cancer therapies. Several Williamson ether techniques were investigated to develop
analogs of solenopsin A to submit for biological testing as antiangiogenic agents.
Computational chemistry techniques were utilized to gain insight into
conformation preferences for the ether products. Each molecule was calculated using
quantum and molecular mechanics in Spartan. The calculations were performed using
equilibrium geometry and the Hartree-Fock model with the 6-31G* basis set. Each
structure was subject to a molecular mechanics conformer search followed by quantum
mechanical calculations for the lowest energy conformers. The dihedral angles were
recorded for each conformer, and again for the minimized conformers.
SYNTHETIC AND MOLECULAR MODELING STUDIES OF ANTIANGIOGENIC
COMPOUNDS BASED ON SOLENOPSIN A LEAD STRUCTURE
by
Shavon L. Ford
A Thesis Submitted to the Faculty of The Graduate School at
The University of North Carolina at Greensboro in Partial Fulfillment
of the Requirements for the Degree Master of Science
Greensboro 2009
Approved by
__________________________________________
Committee Chair
ii
APPROVAL PAGE
This thesis has been approved by the following committee of the Faculty of The Graduate School at The University of North Carolina at Greensboro.
Committee Chair________________________________________________
Committee Members ________________________________________________
________________________________________________
________________________________________________
____________________________ Date of Acceptance by Committee ____________________________ Date of Final Oral Examination
iii
TABLE OF CONTENTS
Page
LIST OF TABLES ............................................................................................................. iv
LIST OF FIGURES .............................................................................................................v
LIST OF SCHEMES.......................................................................................................... vi CHAPTER
I. SYNTHETIC STUDIES OF SOLENOPSIN A ANALOGS .....................................1
Introduction ..................................................................................................1 Background ..................................................................................................1 Results and Discussion ................................................................................7 Experimental Data .....................................................................................17
II. COMPUTATIONAL STUDIES OF SOLENOPSIN A ANALOGS .......................26
Introduction ................................................................................................26 Results and Discussion ..............................................................................32
REFERENCES ..................................................................................................................44
APPENDIX COMPUTATIONAL DATA ........................................................................47
iv
LIST OF TABLES
Page
Table 1. Molecular Modeling Structures…………………….........……………………33
Table 2. Conformer Relative Energies …………………………………………………40
Table 3. Dihedral Angle Data……..………….…………………………...……………43
v
LIST OF FIGURES
Page
Figure 1. Solenopsin Venom ……………………………………………………...………6
Figure 2. N-methyl-2-piperidine methanol……………………………………………......8
Figure 3. Solenopsin A………………………………………………................................8
vi
LIST OF SCHEMES
Page
Scheme 1. sec-Bu Ether ..………………………………………………….……………... 9
Scheme 2. Ethyl Bromide Ether ………………………………………………………… 10
Scheme 3. Elimination Reaction ........................................................................................11
Scheme 4. Methyl Iodide Ether .........................................................................................11
Scheme 5. Tosyl/Mesyl Ethers ..........................................................................................13
Scheme 6. N-Boc Ethers ....................................................................................................15
Scheme 7. N-Boc pyrollidine .............................................................................................16
1
CHAPTER I
SYNTHETIC STUDIES OF SOLENOPSIN A ANALOGS
Introduction The imported fire ants, Solenopsis invicta, were introduced into the United States
by way of Alabama in the mid 1930s. Their devastating impact on the agriculture of the
south led to a project to eradicate them, which in turn resulted in the discovery of the
antiangiogenic activity of a component of their venom. The discovery of 2-methyl-6-
alkyl piperidines has led to the synthesis and study of solenopsin A, trans-2-methyl-6-n-
undecyl piperidine, and analogs. Solenopsin A has proven effective in biological testing
of zebrafish for antiangiogenic studies, thus qualifying it and its analogs as viable
candidates for further studies.
Background
Angiogenesis, a term coined by P. Shubik in 1968, is the growth of blood vessels
from previously existing vessels.1 Angiogenesis is a normal physiological process in
humans during early childhood development, but seldom in adults. It is relatively non-
existent in adults except for menstruation, wound healing, and diseases which are
dependent on vascularization, such as arthritis and diabetes retinopathy.2,3 In both
arthritis and diabetes, new blood vessels form which destroy cartilage and cause
2
blindness, respectively. The dominant disease that is coupled with angiogenesis is
cancer, which progresses through tumor growth.
The role of angiogenesis inhibitors in arresting tumor growth was first hypothesized
by Dr. Judah Folkman in 1971, which was an outgrowth of his observations and G. H.
Algire’s initial idea of tumor growth and the necessity for blood vessels relevancy in
1947.4 Since its discovery, angiogenesis has emerged as a serious target for
understanding the physiology of tumor progression and metastasis, which are “cancerous
cells that have spread to a completely new location”.5 There is an extended amount of
time in which the tumor is not affected by angiogenesis. During this time period a tumor
is able to maintain a limited size of a few millimeters. Once angiogenic properties are
introduced to the tumor, new blood vessels promote tumor growth and ultimately
metastasis.6 There are several important points of Dr. Folkman’s prediction of
angiogenesis dependence which are essential in understanding the fundamentals for the
research and development of potential cancer therapies. These points include the
following: the size and activity of a tumor, such as dormancy which is maintained with a
limited tumor size; tumor masses “activate” angiogenesis; the angiogenesis switch is
triggered by tumor angiogenic factors; tumor growth can be affected by disrupting tumor
angiogenesis; and sustained regression of tumor sizes 1-2mm.1
With the discovery that “angiogenesis plays an important role in cancer from the
initial stage of carcinogenesis to the end stage of metastatic disease”, angiogenesis
inhibition became an aim in cancer therapy.6 Angiogenesis inhibition, also termed
3
antiangiogenesis, appears to have an exciting future in cancer therapy. Antiangiogenic
molecules have been prepared and studied as potential new therapeutics, and they should
be advantageous over the commonly used cancer therapies. Based on previous research,
it has been determined that antiangiogenic techniques are favorable compared to
traditional anti-cancer methods due to its non-problematic interaction with drugs and
lower toxicity effects.7 Some suggested guidelines for the development of antiangiogenic
compounds include low toxicity, prolonged use, drug resistance, and a combination with
cytotoxic therapies.8 A number of notable advantages include tumor specifity, low
toxicity, mainstream of cancer therapy, and continuous dormancy of tumors.7 There are,
however, several limitations along with the advantages of this novel therapeutic method.
Antiangiogenic therapies would require long term treatment, leading to an interaction of
repair and regression, and the drug interaction with long term therapy may not be as
effective as desired.2 The investigation of antiangiogenic compounds commenced nearly
thirty years ago, and the results have yielded both promising and troubling data. The
advantages are worthy of notice, but the discovery of its uses also resulted in problems
with the clinical investigations. The limitations expressed through clinical studies
include lack of rapid transformation of the tumors and the need for combination
treatments with cytotoxic drugs.1 This combination treatment of drugs involves de-
bulking and vascularization inhibition, which is achieved with the cytotoxic and
antiangiogenic therapies, could result in survivors of the disease.9
4
Long term research has produced an antiangiogenic drug phenomenon, such that this
research has become one of the main focuses for cancer therapies. The development of
angiogenic inhibitors through laboratory investigations will need to be clinically
researched for further promotion to clinical trials. With recent discoveries, inhibitors will
be designed with the ideal characteristics in place.
An example of a specific type of cancer that can be positively affected by the use of
antiangiogenic therapies is hepatocellular carcinoma (HCC). HCC is one of the five most
common cancers. This liver disease is associated with cirrhosis and impaired liver
function. The sensitivity and delicacy of the liver makes HCC a very difficult cancer to
treat. Conventional therapies currently consist of “surgical resection, liver transplant,
locoregional therapies, and standard cytotoxic therapies.” Due to the lack of efficacy of
conventional therapies, the investigation of antiangiogenic therapies and their success in
other cancers may prove helpful in the eradication of hepatocellular carcinoma.6
The imported fire ant has played a negative role in the agricultural infrastructure of
the southeastern United States. This formidable pest, which has caused incessant havoc
to crops, livestock, and humans, possesses a key component in its venom that could
potentially cure cancer. The imported fire ant is more formally known as Solenopsis
invicta which originated in Mato Gross, Brazil. Solenopsis invicta was imported into the
United States via Mobile, Alabama between 1933 and 1945. They now occupy states
ranging from the Carolinas to Texas. The limited spread northward is due to the severe
winters which destroy S. invicta’s chances of survival because of their inability to
5
hibernate. Similary, limited spread to the west is due presumably to the harsh desert
climate in Texas.10
The imported fire ant’s presence in the United States has caused a number of serious
problems which include “feeding on plants, stinging of livestock, damage to farm
machinery that strike mounds, loss of hay and grazing area, refusal of workers to enter
heavily infested fields to cultivate or harvest crops, and hazards to human health from
stings that may cause systemic reaction or complications from secondary infections”.10
Although there are a number of problems associated with fire ants, more specifically the
cause of most problems is the use of their potent venom as a defense mechanism. The
venom released from stings may result in allergic reactions such as vomiting, dizziness,
perspiration, and asthma. In severe cases, if medical assistance is not received, the
individual may die. Although painful and potentially deadly, the venom possesses
insecticidal, bactericidal, and fungicidal properties. In efforts to rectify or control the
problem of S. invicta, the venom was investigated and was found to reveal 2-methyl-6-
alkyl piperidines. In the investigation of solenopsin, five components of the venom were
isolated and synthesized: solenopsin A (trans-2-methyl-6-n-undecylpiperidine),1, B
(trans-2-methyl-6-n-tridecylpiperidine),2, and C (trans-2-methyl-6-n-
pentadecylpiperidine),3, as well as dehydrosolenopsin B (trans-2-methyl-6(cis-4-
tridecenyl)piperidine,4, and C (trans-2-methyl-6(cis-6-pentadecenyl)piperidine,5 (Figure
1).10
6
NH
CH3 CH3
NH
CH3 CH3
NH
CH3 CH3
NH
CH3 CH3
NH
CH3 CH3
(1)
(2)
(3)
(4)
(5)
Figure 1: Solenopsin Venom The solenopsin venom of Solenopsis invicta was investigated through sustained
virological response (SVR) angiogenesisis assay to reveal antiangiogenic activity.11 The
assay resulted in inhibition of angiogenesis in zebrafish. Arbiser, Bowen, and
collaborators investigated the bioactivity of the solenopsin venom with Akt, a key
enzyme in angiongenesis, which is involved in proliferation, cytoskeletal organization,
7
survival, and malignant transformation. Due to the fact that Akt plays this particular role
in angiogenesis makes it a logical anticancer treatment target. In order to properly
analyze the potential of solenopsin A, it was necessary to synthesize it and several
derivatives. There were several methods reported and used to synthesize the analogs
which utilize 4-chloropyridine and alkyl magnesium halides as starting reagents in a
subsequent process of N-Boc-piperidine lithiation and methylation, and the procedure of
Beak and Lee.11 The synthesis and testing of solenopsin A and sixteen
tetrahydropyridine analogs as antiangiogenic compounds revealed that only solenopsin A
made a significant difference in the SVR proliferation.
Results and Discussion Several solenopsin A derivatives were envisioned which maintained the
piperidine ring skeleton with variations made only to the side chains. The decision to
implement an oxygen moiety in the side chain is several fold: (1) enhanced activity, (2)
disrupt potential for micelle formation. The synthetic strategy was to use the Williamson
ether synthesis, for preparation of the desired analogs. This approach was chosen based
on assumed ease of synthesis. Ideally, the alkoxide would be formed from use of a strong
base, such as sodium hydride, and the alkylation of the alkoxide would follow with a
simple alkyl halide. The next step would include addition of a long chain carbon to
investigate the biological activity that was documented by Arbiser et al11.
The investigation of solenopsin A derivatives included a thorough search of
scientific databases to verify that these substrates have not been previously synthesized
8
and submitted for antiangiogenic testing. A literature search for comound previously
synthesized did not yield direct procedures for our use; however, modifications were
made based on availability of substrates and reagents, and laboratory conditions.
The investigation of novel analogs began with (1-methylpiperidin-2-yl)methanol,
6, (Figure 2). The goal was to alkylate the side chain using the proposed Williamson
ether synthesis, while ignoring the group previously occupied by the methyl group in
solenopsin A, 1, (Figure 3).
N
CH3
OH
(6) Figure 2: N-methyl-2-piperidine methanol
NH
CH3 CH3(1)
Figure 3: Solenopsin A The initial synthesis consisted of the N-methyl-2-piperdine methanol, 6, and
treatment with sec-butyl bromide. Simple proton-NMR identification was used in an
attempt to identify the ether product (Scheme 1). The procedure was modified from that
of Pan et al.12 The same substrate was again used to develop the ether using a procedure
relayed by Hsiang-Ru Lin et al.13 The difference in procedures included the use of heat
9
and a longer reaction time. Neither reaction yielded the desired products, even though
the TLCs concluded that the reaction was complete. Due to the complexity of the proton
NMR, and, in order to calibrate our results, it was decided to use a simpler alkane, ethyl
bromide, for the modification of the alcohol. The secondary halide was used due to its
ready availability, even though it is ideal to complete a Williamson ether synthesis using
a primary halide.
N
CH3
OH N
CH3
O CH3
CH3
NaH, DMFSec-BuBr
(6) (7)
Scheme 1: sec-Bu Ether
Next, was the use of bromoethane as a substrate utilizing the same starting
material, 5. Several reactions were developed and reported using this compound for ether
preparation. The first of these was by Sallay et al. in which the ethyl ether was not
produced due to the mixture refluxing over night at an extreme temperature and
essentially producing a darkened hard mass that did not yield the desired product
(Scheme 2).14 This procedure was repeated again using a lower temperature but the same
reaction time. The modification also did not yield the product, although the crude
material was an oil instead of a solid substance. With the failure to create the desired
material using the method by Pan et al., the bromoethane was again used in the same
10
procedure as that of the use of sec-butyl bromide. The procedure used for the second sec-
butyl bromide reaction by Hsiang-Ru Lin et al. was used for bromoethane.13 This again
yielded a dark solid substance which is presumably due to the excessive heating for a
prolonged overnight reaction time. Unable to produce the desired material led to the
investigation of another procedure by Boschelli et al.15 Medicinal Chemistry suggested
methodology involved refluxing the reagents before completing the reaction at room
temperature.15 The alternative method involved refluxing the reagents before completing
the reaction at room temperature. Although thin layer chromatography afforded a less
polar spot, which is expected, the desired product was still not produced.
N
CH3
OH N
CH3
O CH3NaH, DMFEtBr100
oC(6) (8)
Scheme 2: Ethyl Bromide Ether In our efforts to further explore the reaction, an eleven carbon chain was then
attempted using 11-chloro-1-undecen in the previously stated procedure15 to assist in the
proton identification of the NMR analysis. The TLC again produced a less polar spot,
but iodine was also used in an attempt to further identify the presence of possible
products that may not be as easily visualized through ultraviolet light or
phosphomolybdic acid. The attempted purification yielded no conclusion as to the
presence of the desired ether.
11
With lack of progress in the derivative synthesis, simultaneous reactions were
performed again utilizing bromoethane. The simplified reactions consisted of running
one at room temperature and the other at approximately 120oC. Still, isolating and
identifying the ether product was illusive. The use of methyl iodide became an option in
trying to understand the complexity of the reaction and possible inter- and intra-
molecular reactions. With the use of iodomethane instead of bromoethane, the possibility
of an elimination reaction could be dismissed (Scheme 3). The use of methyl iodide was
reacted using the same simplified procedure as that of the bromoethane: simultaneous
room temperature and refluxed methods (Scheme 4). This alkyl chain alteration also
proved inconclusive in determining the possible molecular properties present with these
particular substrates.
N
CH3
OH NaH N
CH3
O- Na
+
CH3
Br
H
N
CH3
OHCH3 CH2+
Scheme 3: Elimination Reaction
N
CH3
OH N
CH3
OCH3
NaH, DMF
RT and 120oC
MeI(6) (9)
Scheme 4: Methyl Iodide Ether
12
Another difficulty in isolating any possible product was the excess
dimethylformamide (DMF) present after several workups. The use of other possible
solvents included tetrahydrofuran (THF) and diethyl ether reported by Bream et al.16
proposed using THF in Williamson ether synthesis, which would lower the polarity in
comparison to the use of DMF as a medium.16 THF and ether were used in the same
reaction using bromoethane in which less polar spots were visualized with TLC. LC/MS
and NMR verified the presence of the desired product with the starting material in excess.
It was decided to reproduce the results of the reaction using a diethyl ether medium, with
a higher equivalency of the alkyl halide.
Crown ether was used by Aspinall et al. to produce a Williamson ether products
from hindered alcohols.17 The bromoethane substrate was used and produced a crude
slurry mixture. The use of bromoethane was attempted again using iodomethane and the
crude slurry was treated with HCl/ether to induce crystallization by a procedure noted by
Dr. Scott Furness.18 Another attempt using the ether medium and both alkyl halides was
used in which the sodium hydride, alcohol, and reagent were each concentrated with
ether before addition to the reaction mixture.
With continuous failure of either product formation or isolation of the desired
material, it was decided to transform the hydroxyl group into a mesyl group to enhance
SN2 reactivity. Albrecht et al. performed a protection reactions using mesylchloride.19 In
our experiments, the mesyl chloride and triethylamine were used to create the derivative
alcohol using dichloromethane as the medium instead of DMF, ether, or THF (Scheme
13
5). This was also attempted with tosyl chloride and followed by a replacement by a
litium methoxide.
N
CH3
OH N
CH3
OR
MsCl, Et3NCH2CI2
R=Ms (10), Ts (11)
1) NaBH4 ,THF
30oC
2) MeOLi
N
CH3
OCH3
(6)(9)
Scheme 5: Tosyl/Mesyl Ethers After consultation with thesis committee members, it was determined that the
reaction should be run again but closely monitored with slight alterations in synthetic
techniques, such as making sure the solvents are maintained under anhydrous conditions.
The reaction conditions were altered to include addition of the sodium hydride and
ethylbromide at 0oC to control the reactivity of the substrates in order to prevent an
instantaneous reaction that could possibly lead to unwanted by-products. Additional
sodium hydride was added to react with any water that could possibly be present, and still
allow enough to react with the alcohol. GC/MS was used to monitor the reaction which
yielded the presence of starting material. This reaction was repeated with DMF and
analyzed with GC/MS and NMR to yield the same results, without the presence of
starting material. This reaction was attempted again with a temperature change in which
the mixture was heated to 80oC for 3 hour. An additional equivalency of bromoethane
was added and the reaction continued until completion. This was also performed with the
iodomethane without the additional methyl iodide. Both reactions did not produce the
desired products, which was determined by NMR and GCMS.
14
The final attempt at producing the ether molecule required a change in the starting
material. Perhaps the tertiary nitrogen was undergoing alkylation to give unwanted side
products. It was proposed by a colleague to perform the reaction using a protected form
of the piperidine moiety. Relying on previous experience with similar molecules, it was
concluded that the previous reactions were less likely to form desired material due to
possible formation of quarternary ammonium compounds via N-alkylation. The
possibility of forming the ether from the previous methodologies is still possible,
although purification would be very difficult due to the polarity of the compound. The
idea behind using a protected piperidine is to lower the basicity of the nitrogen in the
ring. The proposed reaction is a two step reaction where each step can be performed in a
one pot synthesis. The first step consists of the formation of the alkoxide using sodium
hydride and an aliphatic compound. This material may, or may not, need to be purified.
The second step consists of removing the BOC protecting group with either HCl/ether or
TFA. Once this has been monitored and verified as deprotected, a methyl group can be
added to the nitrogen using various steps. One suggested method is the use of sodium
borohydro triacetic acid and formaldehyde in dichloromethane (DCM). If the initial
reaction is to be performed successfully, the use of an aromatic instead of aliphatic
compound will render the desired products. The aromatic compound will eliminate the
possibility of quartenary and intramolecular formation.
The reactions utilizing the Boc-protected piperidine were similar to those
performed where the sodium hydride and alkyl halide were separately added at 0oC under
argon (Scheme 6). The temperature was increased to 70oC, and the mixture continued to
15
run until completion; however, the desired product was not detected. In a final
modification of the reaction, it was repeated with a quick one hour reaction time on a
small scale. The alcohol, DMF and sodium hydride were added and allowed to run at
0oC for five minutes before the addition of the ethyl bromide, which only stirred for ten
minutes. This still did not yield the desired material which as determined by NMR.
LC/MS analysis proved the presence of an excess amount of the starting material and the
TLC displayed spots that were more polar, instead of less polar, than that of the starting
material.
N
O O
CH3 CH3
CH3
OHNaH, DMF
MeI and EtBr
N
O O
CH3 CH3
CH3
OR
R=Me (12), Et (13)
Scheme 6 N-Boc Ethers
At this time, another procedure was discovered on similar structures but with a
pyrolidine instead of a piperidine (Scheme 7).20 A small scale reaction was set up
according to the new procedure, and the reaction was run at room temperature for up to
sixteen hours. The TLC of this reaction did not indicate complete transformation of the
starting material to the ether, which led to the decision to remove approximately half of
the material and allow it to react at 80oC until completion.
16
Scheme 7 N-Boc pyrollidine
N-Boc
OH
N-Boc
O
CH3
NaH, THF
MeI(14) (15)
After several attempts using different conditions for various references, it is
concluded that possibly the reaction is best performed with the latest procedure20
containing the Boc protected nitrogen group. The next step will be to perform the same
reaction using an aromatic instead of aliphatic group. Once the procedure is successful, it
will be further optimized to eliminate steps and improve yields.
17
Experimental Data
General Procedures. Anhydrous conditions were utilized, and the atmosphere was under
Argon. Total consumption of the starting material was monitored by thin layer
chromatography (TLC) and the workup is designated under each procedure. The TLCs
were developed with the required solvent polarity and visualized with phosphomolybdic
acid (PMA), iodine crystals, or UV light. The organics recovered from the work up were
dried anhydrous over sodium sulfate (Na2SO4) or magnesium sulfate (Mg2SO4), and the
solvent removed through rotary evaporation. Flash column chromatography on silica gel
was performed to purify the crude material. The products were analyzed by proton and
carbon NMR with deuterated chloroform as the reference. Certain selected reactions
were analyzed using GC/MS and LC/MS.
1-methyl-2-[(1-methylpropoxy)methyl]piperidine (1).
1. Sodium metal in mineral oil (0.48g, 18 mmol) was added to a flask and cooled to
0oC. 4 mL of anhydrous DMF was added and the mixture stirred at 0oC for five
minutes before addition of n-methylpiperidine methanol (1.94g, 15 mmol) via
syringe. The reaction flask was then removed from the ice bath and continued to
stir under argon at room temperature for 1 h. sec-Butyl bromide (2.06g, 15
mmol) in DMF was added, and the reaction continued to stir at room temperature
for 2.5h at which time ethyl acetate and water were used to quench and workup
the crude product.
18
2. sec-Butyl bromide and sodium hydride (in mineral oil) were added to a solution
of n-methylpiperidine-2-methanol and DMF. The mixture was set to reflux
overnight under argon. An additional amount of DMF (5 mL) was added to the
mixture after 2 hours, and the reaction continued to stir for a total reaction time of
18 h. Ethyl acetate and water were used to quench and workup the reaction. The
organics were dried over potassium carbonate (K2CO3), and the solvents
evaporate to yield a brown oil.
2-(ethoxymethyl)-1-methylpiperidine (2).
1. The alcohol (1.29 g, 10 mmol) and 14 ml of DMF were added to a flask, and
sodium metal (0.17g, 7 mmol) was added at 100oC. The temperature of the
solution was raised to 140oC, at which time bromoethane (0.98g, 10 mmol) was
added. The mixture was allowed to stir overnight under argon at this temperature.
The reaction was complete after 24.5 h and was quenched with ethyl acetate and
water. The organics were dried over potassium carbonate, and the solvents
evaporated to yield a crude brown oil.
2. The reaction was reproduced with a temperature alteration that consisted of a
reduction in temperature to RT for 2.5 h before heating to 70oC and allowing to
stir overnight.
3. Sodium hydride (0.48, 18 mmol) and 14 mL of DMF were cooled to 0oC to which
the piperidine alcohol was added and stirred for 5 min. The mixture was warmed
to RT and stirred for 1 h, to which a solution of DMF and ethyl bromide (1.94g,
19
15 mmol) was added. The mixture was allowed to stir overnight under argon, was
quenched with ethyl acetate, and worked up with ethyl acetate and water; then
dried over potassium carbonate.
4. The alcohol (1.26g, 10 mmol), ethyl bromide (1.59g, 10 mmol), sodium hydride
(0.22g, 7 mmol), and 6 mL of DMF were added to a flask and refluxed under
argon overnight. The mixture was quenched with ethyl acetate; the organics
extracted with water and then dried over potassium carbonate.
5. The alcohol (0.165g, 1.28 mmol), ethyl bromide (0.064g, 0.64 mmol), and 6 mL
of DMF were allowed to stir at 125oC for 40 min, at which time sodium hydride
(0.062g, 2.56 mmol) was slowly added. A second portion of sodium hydride
(0.068g, 2.56 mmol) was added after 1h and continued to stir at 125oC for 2 h.
The heat was reduced, and the mixture stirred for 30 min at RT at which time the
reaction was quenched with sodium bicarbonate. The organics were extracted
with dichloromethane and washed with saturated sodium chloride. The organics
were dried over sodium sulfate, and the solvent evaporated to yield a brown oil.
6. The alcohol (0.168g, 1.30 mmol), 4.8 mL of DMF, and sodium hydride (0.079,
2.56 mmol) stirred for 1h at RT before the addition of the ethyl bromide (0.179g,
1.56 mmol). The reaction continued to stir under argon until completion, at which
time saturated sodium bicarbonate was added and stirred for 15 min. The
organics were extracted with dichloromethane, washed with brine, and dried over
sodium sulfate. The solvents were evaporated to yield a crude reddish/brown oil.
20
7. The alcohol (0.180g, 1.39 mmol) and 4.8 mL of DMF were refluxed at 120oC
before the addition of sodium hydride (0.071g, 2.56 mmol) which stirred for 1 h.
The ethyl bromide (0.182g, 1.67 mmol) was added at 110oC and stirred until
completion. The cooled reaction was quenched with sodium bicarbonate and
stirred for 15 min before being extracted with dichloromethane, washed with brie,
and dried over sodium sulfate. The solvents were evaporated to yield a crude
reddish/brown oil.
8. Sodium hydride (0.36g, 15 mmol) and 9.4 mL of THF stirred for 5 min before a
mixture of the alcohol (0.94g, 7.32 mmol) and 4.7 mL of THF was added
dropwise. This mixture stirred at RT for 2 h. At this time, ethyl bromide was
added dropwise, and the mixture continue to stir at RT for 1h. The reaction was
set to reflux and stirred for an additional 2 h. The organics were extracted with
ether and dried over sodium sulfate and concentrated to yield a crude yellow oil.
9. This reaction was run a second time with ether as the solvent instead of THF.
10. Sodium (0.35g, 15 mmol) in 4.8 mL of ether stirred for 5 min, at which time the
alcohol (0.96g, 7.30 mmol) in 9.7 mL of ether was added, followed by crown
ether (1.83 mL, 8.32 mmol). The mixture stirred for 2 h, then ethyl bromide
(1.9g, 10.95 mmol) was added dropwise. The mixture continued to stir at RT
until completion. Brine was added and the organics were extracted with ether,
then dried over sodium sulfate. The concentrated crude oil was dissolved in a
small amount of ether, and HCl in ether was added via pipette. The solvent was
evaporated and additional ether was added to generate crystals by swirling flask.
21
11. Sodium hydride (0.36g, 15 mmol) and 4.83 mL of ether stirred before the addition
of 9.7 mL of ether and alcohol (0.95g, 7.3 mmol). This mixture stirred for 2 h at
RT before the addition of bromoethane (0.96g, 8.8 mmol). An additional amount
of 4 mL of ether was added after 3 h, and the mixture was allowed to stir for the
remainder of the 2 h period. The mixture continued to stir for 2 h after addition of
bromoethane and was quenched with brine. The organics were extracted with
ether and dried over sodium sulfate. They were concentrated to yield a yellow oil.
Ether was added, followed by hydrogen chloride saturated ether to induce
crystallization. This solution sat for 15 min, then was evaporated to yield a
yellow solid. Ether was added and the solution swirled for 15 min, then was
allowed to sit open to atmosphere overnight. This process was done twice to
induce crystallization of the material.
12. The alcohol (0.394g, 3.05 mmol) and 4 mL of THF were cooled to 0oC under
argon for 5 min. Sodium hydride (0.152g, 6.1 mmol) was then added, and the
mixture was warmed to RT and stirred for 15 min. The mixture was cooled 0oC
and ethylbromide (0.665g, 6.1 mmol) was added dropwise. The reaction was
warmed to RT and continued to stir for 4.5 h. Ethyl acetate was added, followed
by the slow addition of water. The organics were extracted with ethyl acetate and
dried over magnesium sulfate. The solvent was evaporated to yield a crude
yellow oil.
13. This reaction was reproduced with the use DMF as a solvent.
22
14. The reaction was again run using DMF, with a change in temperature settings.
The alcohol (0.300g, 2.32 mmol) and 4 mL of DMF were added and stirred for 5
min under argon at 0oC. The sodium hydride (0.111g, 4.64 mmol) was added; the
mixture was warmed to RT and stirred for 1 h under argon. Bromoethane
(0.506g, 4.64 mmol) was added dropwise at 0oC, and the mixture was warmed to
RT and stirred for 1h. The mixture was then heated to 80oC for 3h, at which time
an additional 2 equivalents of bromoethane was added dropwise. The mixture
continued to stir at 80oC for another 3h and 15 min. Dichloromethane and water
were used to quench the reaction. The organics were extracted with
dichloromethane and dried over magnesium sulfate. The solvent was evaporated
to yield a crude yellow oil.
15. This reaction was reproduced with the same solvent and temperature settings and
methyl iodide (0.659g, 4.64 mmol) as the substrate.
2-(methoxymethyl)-1-methylpiperidine (3).
1. The alcohol (0.176g, 1.28 mmol) and 4.8 mL of DMF stirred at RT for 10 min
before the addition of sodium hydride (0.068g, 2.56 mmol), and the mixture was
allowed to stir for 1 h. Methyl iodide (0.224g, 1.54 mmol) was added and stirred
for 2 h at RT, then the reaction mixture was quenched with sodium bicarbonate
which stirred for 15 min. The organics were extracted with dichloromethane,
washed with brine, and dried over sodium sulfate. The organics were
23
concentrated to yield a light yellow oil. The reaction was repeated with sodium
hydride being added at 120oC and the methyl iodide stirred at 110oC.
2. The sodium hydride (0.41g, 15 mmol) and 5 mL of ether stirred for 5 min, at
which time the alcohol (0.94, 7.3 mmol) dissolved in 9.7 mL of ether was added
dropwise. This mixture stirred for 2 h at RT. The methyl iodide (1.25g, 8.8
mmol) was added, and the mixture continued to stir until completion of reaction.
Brine was added, and the organics were extracted with ether. The organics were
dried over potassium and concentrated to yield a crude yellow oil.
(1-methylpiperidin-2-yl)methyl methanesulfonate (4). The alcohol (0.78g, 6.0 mmol),
10 mL of dichloromethane, and triethylamine (1.9 mL, 13.8 mmol) were stirred under
argon at 0oC for 5 min, at which time the mesylchloride (0.57 mL, 7.2 mmol) was added
dropwise. This mixture continued to stir for 1 hr before being quenched with
ammounium chloride, extracted with dichloromethane, and dried over magnesium
sulfate. The solvents were then evaporated to yield a crude oil.
(1-methylpiperidin-2-yl)methyl 4-methylbenzenesulfonate (5). The alcohol (0.78g,
6.0 mmol), triethylamine (1.9g, 13.8 mmol), and 10 mL of dichloromethane were added
and placed under argon at 0oC, at which time tosyl chloride (0.88g, 7.2 mmol) was added.
The mixture continued to stir under argon for 1.5 h before ammonium chloride was used
to quench the reaction. The organics were extracted with dichloromethane and washed
24
with sodium chloride. The organics were dried over magnesium sulfate, and the solvents
evaporated to yield a crude yellow oil and some white crystals.
2-(methoxymethyl)-1-methylpiperidine (3). The tosylate (0.31g, 1.09 mmol), sodium
borohydride (0.102g, 2.19 mmol), and 8 mL of THF were added to a flask and allowed
to stir at RT for 2 h. Lithium methoxide (0.113g, 2.19 mmol) was added after the
reaction stirred for 2 h, and the mixture was allowed to stir for an additional 2 h. Water
was used to quench the reaction, ether was used for the extraction, and the organics were
dried over sodium sulfate and evaporated to yield light a yellow oil.
tert-butyl 2-(methoxymethyl)piperidine-1-carboxylate (6). The alcohol (0.500g, 2.32
mmol) and 4.2 mL of DMF were stirred at 0oC prior to the addition of sodium hydride
(0.120g, 4.64 mmol). The mixture continued to stir at RT under argon for 1 h. Methyl
iodide (0.659g, 4.64 mmol) was added at 0oC, and the mixture was warmed to RT and
stirred for 1 hr. The temperature was raised to 70oC and continued to stir until an
additional equivalent of methyl iodide was added and the reaction continued to stir at
60oC until completion. Water and dichloromethane were added to quench the reaction.
Dichloromethane was used to extract the organics which were dried over magnesium
sulfate. The solvent was evaporate to yield a reddish brown oil.
tert-butyl 2-(ethoxymethyl)piperidine-1-carboxylate (7). The alcohol (0.100g, 2.32
mmol), 2 mL of DMF, and sodium hydride (0.50g, 11.6 mmol) stirred for 5 min at 0oC, at
25
which time the ethyl bromide (0.659g, 4.64 mmol) was added and stirred for 10 min
before being worked up with methanol. The organics were extracted with water and
ether and dried over magnesium sulfate. The solvent was evaporated to yield a crude
yellow oil.
26
CHAPTER II
COMPUTATIONAL STUDIES OF SOLENOPSIN A ANALOGS
Introduction
Computational chemistry has developed over an extended period of time, and it
may now be considered one of the main branches of chemistry. The origins may be
traced in part to molecular modeling in the form of handheld mechanical models. The
importance of visualizing molecular structures extends beyond simply understanding the
atomic connectivity to include energy, physical properties, and possible interactions with
other molecular systems. Investigating these properties may lead to a better
understanding of a molecule’s potential as a possible drug lead, as well as synthetic
feasibility. Structure activity relationships (SARs) can be predicted and used in drug
design. One example of a beneficial development in computational chemistry
methodology has been the calculation of relative free energies of inhibitors binding to
HIV-1 protease.21 The interactions were estimated through use of hydrophobic surface
property maps between the inhibitors and binding sites of the protease.21
Molecular visualization finds a natural and central place in medicinal chemistry
research. Implementing calculations for specific products or transition state molecules
have assisted medicinal chemists to design potential therapeutic agents. Computational
chemistry predictions may be derived from structural-based determination of ideal
27
molecules in which the lowest energy is calculated along with chemical properties (e.g.
NMR chemical shifts, ionization potentials, and electronic spectra).22
The use of structure based drug design, where appropriate, is also an important
goal for medicinal chemists to develop potential drug candidates. The ability to visualize
properties aids in the molecular design process.21 Utilizing molecular modeling can
assist in the avoidance of wasted efforts in time and money preparing unrealistic
synthetic targets. The concept of molecular modeling involves the use of molecular
design and computational studies to predict properties essential for drug receptor
interactions, such as molecular geometries, energetic, chemical reaction pathways,
ADME (absorption, distribution, metabolism, elimination), and biological responses
(CADD) and usually involves simplifying approximations of a more general theory to
extend its practical utility.22 Computational chemistry developments allow for more
accurate calculations due to the increase of computer speeds and more reliable potential
energy functions.21
Quantum and molecular mechanics are the foundations of computational
chemistry. These calculations are used to study potential drug candidates in silico. Both
computational methods are based originally on gas phase equations, where each
Individual approach is separately applied according to the specific calculation
requirements, which can include the geometry, energy, surface area, dipole moments, etc.
The selection of an appropriate method is determined by the size of a particular molecular
system and the research goals. Larger molecules are best investigated with molecular
28
mechanics, while a smaller system uses quantum mechanical calculations.22 Quantum
mechanics consists of three different methods, ab initio, density functional theory (DFT),
and semi-empirical methods. Ab initio which is Latin for “from the beginning” involves
calculations that are solely based on theory and not experimental application, although
there are some simplifying approximations. Density functional theory investigates
electronic structures through properties that are derived from the use of electronic density
function. Semi-empirical methods consist of brutal approximations, which omit key
integrals that leads to calculations which are faster than ab initio, but the answers are
crude and only qualitative at best. Overall, applications are used for a particular
calculated problem.
Alternatively, molecular mechanics is particularly suited for drug design
investigations, and it is the basis for many CADD methods. It may be defined as a
mathematic approach used to calculate the structures and associated energies of
molecular systems.23 The force field, which is a set of parameters and equations used to
determine the potential energy of a molecule, yields desired information about physical
properties that may lead to insight into the bioactive conformations. A fundamental
concept in molecular mechanics is the distribution of the total energy of a molecular
system into potential functions associated with bending, stretching, and nonbonded
energies.
Medicinal chemists use computational chemistry to better understand lead-target
interactions. Understanding bioactive conformations involves gathering information
29
from different aspects, such as structure-function relationships.24 An economic
motivation for using computational methods is to explore molecular properties prior to
experimental work. The goal is to minimize the time and expense of laboratory
preparations and evaluations. The uses of computational chemistry extend beyond the
calculation of gas phase molecular structures to include energetically favorable
conformations and ADME/Tox properties.
The piperidine moiety has proven important throughout chemical history as a
biologically active unit. Further exploration can only continue to prove itself more
useful. This valuable heterocycle has been studied and decided through experimental
investigation to be clinically useful in treating infections, schizophrenia, and Parkinson’s
disease; as well as a more recent discovery of its functions with cocaine abuse
medications.25 Due to the various applications of the synthetic compounds that consist of
the piperidine component, necessary molecular modeling calculations have been carried
out to further investigate the properties of piperidines and its derivatives.
Important studies were undertaken that focused on the nitrogen and the placement
of methyl substituents on different ring positions. These are important to the
investigation of solenopsin A analogs which contain some form of the previously
investigated compounds. The piperidine ring was studied with emphasis placed on the
nitrogen moiety by Lobato-Garcia, et al. who focused on the conformational energies.26
The importance of focusing on a molecule’s ability to alter its conformational states
provides insight into its binding affinity and affords the lowest possible energy of the
30
molecule.21 Three noteworthy items were observed in this study: quantum chemical ab
inito calculations have afforded relation between nitrogen inclusion and biological
effects; “polarized basis sets” are also useful for the conformational studies; ab initio and
density functional theory (DFT) were used to calculate minimum energies and
thermodynamic properties. The conformational distributions energies were calculated
using the Monte Carlo method, of which further minimization was completed using the
B32YP method and 6-311G basis set. These conformers were selected for each
compound in question to yield a conclusive presentation of a chain conformation of the 6-
membered piperidine ring. There are some important observations from the data, such as
the equatorial position of the substituents on nitrogen in the piperidine is referenced as
being “generally accepted by 6-membered saturated cycles”.26 An important observation
is the interaction of the oxygen within the “spatial proximity” of the hydrogen, which is
indicative of weak intramolecular hydrogen bonding. The interaction between the
nitrogen and hydrogen is also significant in the illustration of conformational energy
stability. The dihedral angles were also investigated to further support the conclusion
concerning the stabilities of the conformers. The conclusion from the Lobato-Garcia
study attributes the conformational differences to the “spatial disposition of substituents”,
with noted interest on the “diasterotopic hydrogen” of these conformers.26
Another important study concerning the piperidine moiety was done by Ribiero
de Silva et al., who focused on the thermochemistry and conformational stability of
methylpiperidines.25 The energy of combustion investigation of these derivatives
31
consisted of obtaining commercially available samples of the methyl piperidines which
were measured by combustion calorimetry: 1-methylpiperidine, 3-methylpiperidine, 4-
methylpiperidine, 2,6-dimethylpiperinde, and 3,5-dimethylpiperidine. The relevance of
this study is fueled by the published work that analyzes the conformational stability of
piperidine derivatives. The thermochemistry work has also been investigated for this
motif by utilizing computational theories, such as ab initio and DFT. In de Silva’s
particular study, only the axial conformers were considered; they were found to be less
stable than equatorial, which was also shown in the results of Lobato-Garcia et al.26 De
Silva’s work also proved that the MP2/6-31G* method is a more accurate approach to
investigate piperidine conformers. With this additional motivation for the study, the
methyl piperidine derivatives were investigated using MP2, BP86, and B3LYP methods
with the 6-31G(d) basis set. The study illustrated the stabilities of the derivatives in
comparison with the axial and equatorial conformations. It was concluded that “all
compounds are more stable when in the equatorial and chair conformations”.25 The
geometrical calculations also afforded results “suggesting the space occupied by [the]
methyl group is smaller than an unsubstituted nitrogen in the piperidine ring”.25 The
calculation of the enthalpy of formation is in agreement with the results of the
conformational studies. The results from this study lead to a conclusive determination
that the ring is more stable with nitrogen unsubstituted and the varying placements of
methyl groups around the ring.
32
Results and Discussion
Computational chemistry techniques were employed to gain insight into
conformational preferences for the piperidine ether analogs. Each structure was
calculated using quantum and molecular mechanics in Spartan. The calculations were
carried out using the equilibrium geometry options and the Hartree-Fock model with the
6-31G* basis set. Each structure was subjected intially to a molecular mechanics
conformer search, followed by quantum mechanical calculations of the lowest energy
conformers (Table 2). The dihedral angles were recorded for each conformer, and again
for the minimized conformers. These molecules have been compared to solenopsin A to
establish some understanding of the role the oxygen plays in conformational stability and
the interconversion of one conformer into another. The molecules submitted for energy
calculations include N-substituted and non-substituted piperidines. The substituents on
the oxygen and nitrogen moieties vary from simple ethyl chains to aromatic groups
(Table 1). The molecules in the first set of calculated energies include substituted and
non-substituted piperidines with the methyl oxygen ethers: 9, 2-(methoxymethyl)-1-
methylpiperidine; 16, 2-(ethoxymethyl)-1-methylpiperidine;17, 2-(methoxyundecyl)-1-
methylpiperidine; 18, (1-methylpiperidin-2-yl)methyl methanesulfonate; 19, (1-
methylpiperidin-2-yl)methyl 4-methylbenzenesulfonate; 20, 2-
(methoxymethyl)piperidine; 21, 2-(ethoxyethyl)piperidine; 22, 2-
(methoxyundecyl)piperidine;23, 2-(piperidin-2-yl)methyl methanesulfonate; 24,
piperidin-2-ylmethyl 4-methylbenzenesulfonate.
33
The second data set includes commercially available compounds and their desired
synthetic products: 25, N-boc-piperidine-2-methanol; 26, N-boc-piperidine-2-ethanol; 27,
N-boc-piperidine-2-ethoxymethyl; 28, N-boc-piperidine-2-ethoxymethyl. Commercially
available derivatives were purchased for biological testing: 29, 2-(2-
methoxyethyl)piperidine; 30, 2-(2-ethoxyethyl)piperidine; 31, 2-[2-
(benzyloxy)ethyl]piperidine; 32, 2-(2-propoxyethyl)piperidine; 33, 2-[2-(3-
phenylpropoxy)ethyl]piperidine. The fourth set consisted of a nitrogen instead of oxygen
moiety: 34, N,N-diethyl-2-piperidin-2-ylethanamine; 35, N,N-dimethyl-2-piperidin-2-
ylethanamine; 36, 4-methyl-1-(2-piperidin-2-ylethyl)piperidine; 37, 1-(2-piperidin-2-
ylethyl)piperidine; 38, 1-(2-piperidin-2-ylethyl)azepane; 39, 2-(2-pyrrolidin-1-
ylethyl)piperidine. All of the analogs are derived from the solenopsin A lead structure:
40, trans-2-methyl-6-n-undecylpiperidine.
Table 1: Molecular Modeling Structures
Structure
N
CH3
OCH3
9
N
CH3
O CH3
16
34
Structures Continued
N
CH3
OCH3
17
N
CH3
OS
O
OCH3
18
N
CH3
OS
O
O
CH3 19
N
H
OCH3
20
N
H
O CH3
21
35
Structures Continued
N
H
OCH3
22
N
H
OS
O
OCH3
23
N
H
OS
O
O
CH3 24
N
BOC
OH
25
N
BOC
OH
26
36
Structures Continued
N
BOC
OCH3
27
N
BOC
OCH3
28
NH
OCH3
29
NH
O CH3 30
NH
O
31
NH
OCH3
32
37
Structures Continued
NH
O
33
NH
N CH3
CH3 34
NH
NCH3
CH3 35
NH
N CH3
36
NH
N
37
38
Structures Continued
NH
N
38
N
N
H 39
NH
CH3 CH340
The first set of molecules, 1 through 10, to undergo energy calculations consisted
of substituted and un-substituted piperidine molecules where the side chain contains an
oxygen with various alkyl groups. The lowest energy molecule in the set of un-
substituted and methylated piperidines is the tosylate protected oxygen, with quantum
energies of -1179.82 au and -1218.85 au, respectively. As expected, the lowest energy
conformer of each molecule in the first data set for both piperidine groups illustrate that
the methyl-substituted nitrogen of the piperidine moiety produces a lower quantum
energy value. Solenopsin A has a HF energy of -718.61 au for its lowest energy
39
conformer. The lowest conformer energies are shown in relation to the lowest relative
energies (Table 2).
Failure to produce results from the initial synthesis of the Williamson ether
compound from 2-piperidine methanol led to the investigation of another substrate, N-
boc-piperidine-2-methanol. 11 was utilized in the lab and also submitted for energy
calculations through molecular modeling. The second data set consists of the two
commercially available Boc-protected piperidines (11,12) and the desired alkylated ether
products (13,14) (Table 1). The methyl component of the starting material and product
yielded HF energies of -707.84 au and -746.86 au, respectively. The ethyl component
afforded -746.87 au and -785.89 au for the starting material and product. The lowest
energy conformers of each molecule were calculated using the Hartree-Fock method
(Table 2).
The third and fourth data sets are a combination of commercially available
derivatives, some of which have been purchased and submitted for biological testing
against the Akt enzyme for anti-angiogenic activity using the SVR assay. The molecules
in the third data set still contain the oxygen functionality and a non-substituted nitrogen,
with variations in the chain which include aliphatic and aromatic groups (15-19). The
lowest energy molecule calculated is the 2-(3-phenylpropoxy)ethyl piperidine of -749.75
au (Table 2). All of these molecules, with the exception of 2-benzyloxyethylpiperidine
(17), have been submitted for biological testing with pending results.
40
The fourth, and final, data set consists of a nitrogen in place of an oxygen moiety
(20-24). Only two items from this set were purchased and submitted for testing with
pending biological results: diethyl-2-piperidine ethyl amine, 20, and dimethyl-2-
piperidine methyl amine, 21 (Table 1). The minimized conformers have been listed with
their relative energies. No comparison has been made, but the data has been collected for
possible use in further investigations (Table 2).
Table 2: Conformer Relative Energies
Structure Number
Conformer 1
Conformer 2
Conformer 3
Conformer 4
Conformer 5
9a 0.0030 0.0000* 0.0046 0.0052 N/A
16b 0.0000* 0.0019 0.0030 0.0026 0.0026
17c 0.0000* 0.0001 0.00197 0.0040 0.00207
18d 0.0006 0.0009 0.000* 0.0010 0.0029
19e 0.0012 0.000* 0.0010 0.0007 0.0012
20f 0.000* 0.0030 0.0040 0.0070 0.0010
21g 0.000* 0.0024 0.00257 0.002581 0.000*
22h 0.0002 0.000* 0.0015 0.0019 0.0017
23i 0.000* 0.0030 0.0020 0.0060 0.0060
41
24j 0.000* 0.00170 0.00160 0.0050 0.0032
25k 0.000* 0.002943 0.002942 0.00689 N/A
26l 0.00149 0.000* 0.00170 0.000798 0.00192
27m 0.000* 0.002446 0.005050 0.007948 0.00804
28n 0.000155 0.0011 0.000* 0.002729 0.003728
29o 0.000* 0.000868 0.002737 0.003342 0.001681
30p 0.000* 0.000871 0.002603 0.002715 0.002635
31q 0.000* 0.000214 0.000388 0.003466 0.001105
32r 0.000285 0.000149 0.000082 0.000236 0.000*
33s 0.000106 0.0001 0.001489 0.001508 0.000*
34t 0.003011 0.003679 0.004057 0.000* 0.001952
35u 0.000* 0.00027 0.001049 0.002008 0.001965
36v 0.001971 0.000* 0.001971 0.004087 0.005715
37w 0.000* 0.000931 0.00200 0.005372 0.006304
38x 0.001925 0.003584 0.002154 0.000* 0.001018
42
39y 0.000* 0.000249 0.001914 0.005209 0.006531
40z 0.000* 0.00020 0.0017 0.0016 0.0021
*a: 2, -442.1250 au; b: 1, -481.1648 au; c: 1, -832.479 au; d: 3, -989.3086 au; e: 2, -1218.8538 au; f: 1, -403.101 au; g: 1,5, -442.1409 au; h: 2, -793.4569 au; i: 1, -950.286; j: 1, -1179.8173 au; k: 1, -707.84729 au; l: 2, -746.87119 au; m: 1, -746.86715 au; n: 3, -785.8997 au; o: 1, -442.13576 au; p: 1, -481.17579 au; q: 1, -671.684248 au; r: 5, -520.21078 au; s: 5, -749.75684 au; t: 4, -539.403226 au; u: 1, -461.33439 au; v: 2, -616.31814 au; w: 1, -577.2840 au; x: 4, -616.307361; y: 1, -538.24355; z: 1, -718.6100 au
The dihedral angles were recorded for each molecule and the individual energy
conformers were submitted for quantum calculations. The torsion angles relate to the
chemical bonds that intersect the plane, while the bond angles relate to the electronic
pairs in the valence shell. The independent parameters that are visualized correlate to
conformations such as chair, which is almost free of strain and boat, which is free of
angle strain. There are some noticeable differences in the dihedral angles of the
minimized conformers, although a direct comparison or conclusion has not been
determine. The dihedral angles of methylated and non-substituted piperidines with the
oxygen and carbon moieties were investigated and the initial angles were documented,
followed by the parameters of the minimized conformers, which are in parentheses
preceding the original conformer values. These values were calculated at the set dihedral
angles of 30 o, 60 o, 90 o, 120 o, and 180o (Table 3).
43
Table 3: Dihedral Angle Data
Structure Energy (au) 30o
Energy (au) 60 o
Energy (au) 90 o
Energy (au)120 o
Energy (au)180 o
N
H
OCH3
-403.0993 -403.0993 -403.0993 -403.0993 -403.1021
N
H
CH3
-367.2925 -367.2849 -367.2925 -367.2942 -367.2942
N
CH3
OCH3
-442.1236 -442.1236 -442.1248 -442.1263 -442.1263
N
CH3
CH3
-406.3162 -406.3129 -406.3162 -406.3178 -406.3179
44
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20. Klaus Kopka, Andreas Faust, Petra Keul,|, Stefan Wagner, Hans-Jo¨rg Breyholz, Carsten Ho¨ltke, Otmar Schober, and a.B.L. Michael Scha¨fers, 5-Pyrrolidinylsulfonyl Isatins as a Potential Tool for the Molecular Imaging of Caspases in Apoptosis. Journal of Medicinal Chemistry, 2006, 49, 6704-6715.
21. Tami J. Marrone, J.M.B., and J. Andrew McCammon, STRUCTURE-BASED
DRUG DESIGN: Computational Advances. Annual Review of Pharmacological Toxicology, 1997, 37, 71-90.
22. Cramer, C.J., Essentials of Computational Chemistry: Theories and Models. 2002: John Wiley and Sons, LTd.
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23. Computational Chemistry and Computer-Assisted Drug Design,” Bowen, J. P. In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. Delgado, J. N.; Remers, W. A. Lippincott Williams & Wilkins: Philadelphia 2004 pp 919-947.
24. Phillip Bowen, P., Paul S. Charifson, PhD, Peter C. Fox, BA, Maria Kontoyianni, PhD,, P. Aaron B. Miller, Dora Schnur, PhD, Eugene L. Stewart, BS,, and P. and Christopher Van Dyke, Computer-Assisted Molecular Modeling: Indispensable Tools for Molecular Pharmacology. The Journal of Clinical Pharmacology, 1993, 33, 1149-1164.
25. Vilkov, E.G.A.a.L.V., Dihedral Angles in Cyclic Molecules. Journal of Structural Chemistry, 2003, 44, 846-851.
26. Carlos E. Lobato-Garcı´a a, Patricia Guadarrama b, Concepcio´n Lozada a, Rau´l G. Enrı´quez a,*, and W.F.R. Dino Gnecco c, Study of minimum energy conformers of N-substituted derivatives of piperidine and pyrrolidine. Evidence of weak H-bonding by theoretical correlation with experimental NMR data. Journal of Molecular Structure, 2006, 786, 53-64.
47
APPENDIX
COMPUTATIONAL DATA
Compound 20
N
H
OCH3
Molecule (-403.10 au) E gas(kcal/mol) Rel. E gas(kcal/mol) Conformer.1 22.79356 0Conformer.2 23.89023 1.09667Conformer.3 24.53839 1.74483Conformer.4 25.81579 3.02223Conformer.5 28.34086 5.5473Conformer.6 28.47425 5.68069
minimized conformers mepconf# Relative Energy (kcal/mol) Conformer.1 -403.101 0 Conformer.2 -403.098 0.003 Conformer.3 -403.097 0.004 Conformer.4 -403.094 0.007 Conformer.5 -403.100 0.001 Conformer.6 -403.090 0.011
Dih(C5,C4,C3,C2) Dih(C4,C3,C2,C1) Dih(C3,C2,C1,N1) Conformer 1 (52.81) 51.9263 (-52.06) -51.745 (53.05) 55.8437Conformer 2 (52.89) 52.0037 (-52.24) -52.015 (52.99) 55.8381Conformer 3 (-52.35) -52.113 (53.76) 52.1869 (-55.66) -54.743Conformer 4 (-52.37) -52.509 (54.10) 52.5137 (-55.81) -54.625
48
Conformer 5 (52.76) 53.0312 (-52.65) -51.398 (53.71) 55.1405Conformer 6 (-52.51) -51.469 (52.97) 51.6152 (-56.08) -55.462
Dih(C2,C1,N1,C5) Dih(C1,N1,C5,C6) Dih(N1,C5,C6,O1) Conformer 1 (-54.70) -59.531 (-178.83) -177.7 (175.74) 176.704Conformer 2 (-54.29) -59.054 (-179.94) -178.51 (179.12) -179.28Conformer 3 (58.98) 56.9949 (70.89) 71.8734 (171.07) 171.353Conformer 4 (58.70) 56.3561 (70.96) 72.644 (175.40) 177.864Conformer 5 (-54.68) -60.292 (179.75) -177.17 (171.66) 142.878Conformer 6 (61.73) 59.159 (38.91) 69.7338 (135.38) 134.198
*(xxx) relates to the dihedral angles of the minimized conformers
Compound 9
Molecule (-442.13aul) E gas(kcal/mol)
Rel. E gas(kcal/mol)
Conformer.1 32.105773 -0.642508999Conformer.2 32.748282 0Conformer.3 34.831071 2.082789Conformer.4 35.696259 2.947977
N
CH3
OCH3
49
minimized conformers (au) relative energy (kcal/mol)
Conformer.1 -442.1220 0.0030Conformer.2 -442.1250 0.0000Conformer.3 -442.1204 0.0046Conformer.4 -442.1198 0.0052Dih(C6,C5,C4,C3) Dih(C5,C4,C3,C2) Dih(C4,C3,C2,C1) Dih(C3,C2,C1,N1)(-179.67) -177.340 (-53.76) -53.934 (54.29) 54.227 (-57.42) -56.972(-178.09) -176.933 (-53.12) -53.762 (52.35) 52.868 (-56.35) -56.035
(82.84) 80.852 (49.57) 47.478 (-52.93) -49.642 (56.00) 54.220(-177.71) -176.204 (-54.00) -53.385 (53.87) 53.922 (-56.61) -56.697
Dih(C2,C1,N1,C8) Dih(C1,N1,C8,C5) Dih(C8,N1,C5,C6) Dih(N1,C5,C6,O1)(-175.77) -178.079 (-125.77) -123.673 (57.89) 58.013 (72.22) 77.307(-170.34) -175.195 (-127.81) -124.839 (49.04) 54.423 (57.41) 61.390
(77.81) 72.655 (-131.77) -126.826 (145.28) 154.127 (73.44) 78.252(-174.55) -177.504 (-126.51) -124.343 (51.16) 54.512 (36.31) 34.198
Dih(C7,O1,C6,C5) Dih(O1,C6,C5,C4)
(-85.84) -85.838 (-52.27) -52.262
(176.90) 176.903 (-66.20) -66.202
(-178.64) -178.636 (-57.00) -57.005
(68.69) 68.694 (-89.66) -89.663
Compound 16
N
CH3
O CH3
50
Molecule (-481.165 au) Egas(kcal/mol)
Rel. Egas (kcal/mol)
Conformer 1 28.94606 0Conformer 2 29.842155 0.896094999Conformer 3 30.078489 1.132429Conformer 4 30.357828 1.411768
5 30.503007 1.5569476 30.686032 1.7399727 31.04085 2.094798 31.336442 2.3903829 31.415937 2.469877
10 31.682369 2.73630911 32.265824 3.31976412 32.533464 3.58740413 32.570324 3.62426414 33.185804 4.2397439915 35.497538 6.5514779916 37.397392 8.45133199
minimized conformers nmpe# relative energies (kcal/mol)
Conformer 1 -481.1648 0Conformer 2 -481.1629 0.0019Conformer 3 -481.1618 0.003Conformer 4 -481.1622 0.0026Conformer 5 -481.1622 0.0026
Dih(C8,C7,O1,C6) Dih(C7,O1,C6,C5) Dih(O1,C6,C5,C54) Dih(C6,C5,C4,C3)(179.91) -179.984 (-179.05) 179.323 (-62.82) -57.720 (-75.21) -73.521(179.70) -179.713 (179.28) -178.526 (-66.32) -62.732 (176.72) 177.363(178.77) -176.473 (-90.24) -76.717 (-61.14) -51.395 (-75.26) -73.615
(-79.76) -82.833 (-175.64) 178.137 (-63.07) -57.911 (-75.15) -73.406(78.61) 78.9211 (175.85) 176.111 (-63.11) -57.812 (-75.25) -73.519
51
Dih(C5,C4,C3,C2) Dih(C4,C3,C2,C1) Dih(C3,C2,C1,N1) Dih(C2,C1,N1,C9)(-53.06) -53.041 (52.79) 51.436 (-54.24) -54.003 (-166.55) -173.057
(52.04) 51.402 (-51.25) -51.182 (54.39) 54.262 (75.72) 72.857(-52.91) -53.385 (52.89) 51.774 (-54.95) -53.972 (-166.61) -173.788(-53.12) -53.110 (52.79) 51.440 (-54.16) -53.941 (-166.69) -173.159(-53.02) -53.036 (52.75) 51.414 (-54.25) -53.997 (-166.41) -173.011
Dih(C1,N1,C9,C5) Dih(C9,N1,C5,C6) Dih(N1,C5,C6,O1) (-136.10) -128.559 (-63.99) -59.194 (171.61) 176.857(-129.54) -126.459 (54.51) 55.439 (165.09) 168.967(-136.01) -128.383 (-64.17) -58.146 (173.52) -177.120(-136.13) -128.548 (-64.02) -59.255 (171.40) 176.732(-136.15) -128.569 (-64.07) -59.238 (171.29) 176.778
Compound 17
N
CH3
OCH3
Molecule (-832.47 au)
E gas(kcal/mol)
Rel. E gas(kcal/mol)
Conformer.1 25.467395 0Conformer.2 25.573465 0.10607Conformer.3 26.242585 0.77519Conformer.4 26.586159 1.11876Conformer.5 26.664844 1.19745Conformer.6 26.753604 1.28621Conformer.7 26.883468 1.41607Conformer.8 26.941514 1.47412Conformer.9 27.128355 1.66096Conformer.10 27.188595 1.7212Conformer.11 27.25029 1.7829Conformer.12 27.335113 1.86772Conformer.13 27.364056 1.89666
52
Conformer.14 27.387829 1.92043Conformer.15 27.419696 1.9523Conformer.16 27.425772 1.95838Conformer.17 27.432298 1.9649Conformer.18 27.487249 2.01985Conformer.19 27.490835 2.02344Conformer.20 27.378633 1.91124Conformer.21 27.681796 2.2144Conformer.22 27.69354 2.22615Conformer.23 27.716514 2.24912Conformer.24 27.788052 2.32066Conformer.25 27.809584 2.34219Conformer.26 27.877863 2.41047Conformer.27 27.759932 2.29254Conformer.28 27.960189 2.49279Conformer.29 28.209207 2.74181Conformer.30 28.247731 2.78034Conformer.31 28.266604 2.79921Conformer.32 28.439723 2.97233Conformer.33 28.41407 2.94668Conformer.34 28.525284 3.05789Conformer.35 28.538964 3.07157Conformer.36 28.563312 3.09592Conformer.37 28.64869 3.1813Conformer.38 28.801955 3.33456Conformer.39 28.968545 3.50115Conformer.40 29.015213 3.54782Conformer.41 29.061018 3.59362Conformer.42 29.377953 3.91056Conformer.43 29.413483 3.94609Conformer.44 29.546582 4.07919Conformer.45 29.673079 4.20568Conformer.46 29.792069 4.32467Conformer.47 29.994905 4.52751Conformer.48 30.018223 4.55083Conformer.49 30.044266 4.57687Conformer.50 30.144381 4.67699
53
Conformer.51 30.196134 4.72874Conformer.52 30.284006 4.81661Conformer.53 30.175609 4.70821Conformer.54 30.372511 4.90512Conformer.55 30.640503 5.17311Conformer.56 30.682964 5.21557Conformer.57 30.812927 5.34553Conformer.58 30.822241 5.35485Conformer.59 30.856155 5.38876Conformer.60 30.955668 5.48827Conformer.61 31.087691 5.6203Conformer.62 31.182519 5.71512Conformer.63 31.385519 5.91812Conformer.64 31.593603 6.12621Conformer.65 31.70339 6.23599Conformer.66 31.894705 6.42731Conformer.67 3123.4643 3098Conformer.68 32.184789 6.71739Conformer.69 32.192694 6.7253Conformer.70 32.246917 6.77952Conformer.71 32.25027 6.78287Conformer.72 32.469786 7.00239Conformer.73 32.585495 7.1181Conformer.74 32.620119 7.15272Conformer.75 32.601492 7.1341Conformer.76 32.648794 7.1814Conformer.77 32.734337 7.26694Conformer.78 32.739353 7.27196Conformer.79 32.992146 7.52475Conformer.80 33.084295 7.6169Conformer.81 33.112302 7.64491Conformer.82 33.259114 7.79172Conformer.83 33.362725 7.89533Conformer.84 33.399948 7.93255Conformer.85 33.416667 7.94927Conformer.86 33.642445 8.17505Conformer.87 33.667171 8.19978
54
Conformer.88 33.763939 8.29654Conformer.89 33.960883 8.49349Conformer.90 34.073025 8.60563Conformer.91 34.133318 8.66592Conformer.92 34.529473 9.06208Conformer.93 34.580281 9.11289Conformer.94 34.66889 9.20149Conformer.95 34.785203 9.31781Conformer.96 35.05174 9.58434Conformer.97 35.05174 9.58434Conformer.98 35.120454 9.65306Conformer.99 35.340049 9.87265Conformer.100 35.465196 9.9978
minimized conformers nmpu#
relative energies (kcal/mol)
Conformer.1 -832.479 0Conformer.2 -832.478 0.001Conformer.3 -832.47703 0.00197Conformer.4 -832.475 0.004Conformer.5 -832.47693 0.00207
Dih(C17,C16,C15,C14) Dih(C16,C15,C14,C13) Dih(C15,C14,C13,C12) Dih(C14,C13,C12,C11)
(-179.92) -180 (179.89) -180 (179.85) -180 (179.88) 180(-180.00) 180 (-179.97) 180 (179.99) -180 (-179.99) 179.999
(179.79) 179.845 (175.80) 175.277 (66.05) 66.009 (175.44) 175.289(179.87) 180 (179.92) 180 (179.75) 179.993 (179.78) 179.996
(-179.99) -180 (179.99) -179.98 (-179.74) -179.84 (-175.85) -175.28
55
Dih(C13,C12,C11,C10) Dih(C12,C11,C10,C9) Dih(C11,C10,C9,C8) Dih(C10,C9,C8,C7) (179.83) -180 (179.80) -180 (179.78) 179.975 (-179.91) -178.62
(179.93) -179.99 (179.90) 179.986 (-180.00) -179.91 (-178.80) -178.28(179.69) 179.832 (179.75) 179.984 (-179.99) 179.994 (179.12) 178.651(179.39) 179.786 (174.80) 175.397 (61.45) 59.8483 (62.40) 59.3196(-66.23) -66.001 (-175.74) -175.29 (-179.74) -179.82 (179.74) 178.656
Dih(C9,C8,C7,O1) Dih(C8,C7,O1,C6) Dih(C7,O1,C6,C5) Dih(O1,C6,C5,C4)(-63.56) -63.623 (179.02) 179.703 (-179.84) 177.693 (-55.48) -58.369(-63.32) -63.085 (-176.74) 179.488 (179.50) -176.12 (-152.09) -155.99(64.08) 63.4397 (-179.89) -179.27 (-177.88) 176.927 (-55.16) -58.267
(174.82) 175.611 (179.64) 179.979 (-179.39) 177.418 (-55.26) -58.469(63.33) 63.5419 (-178.04) 179.886 (-179.85) -177.24 (-153.24) -156.17
Dih(C6,C5,C4,C3) Dih(C5,C4,C3,C2) Dih(C4,C3,C2,C1) Dih(C3,C2,C1,N1)(-177.95) -179.77 (53.65) 53.1557 (-53.14) -53.373 (56.63) 57.1253(-178.06) 179.095 (53.07) 53.487 (-52.71) -52.385 (56.84) 56.3778(-177.75) -179.74 (53.60) 53.1462 (-53.17) -53.376 (56.69) 57.1297(-177.95) -179.77 (53.66) 53.161 (-53.16) -53.37 (56.66) 57.1228(-178.22) 179.115 (53.06) 53.4944 (-52.68) -52.417 (56.84) 56.396
Dih(C2,C1,N1,C18) Dih(C18,N1,C5,C6) Dih(N1,C5,C6,O1) (173.02) 176.517 (-55.32) -58.584 (-177.42) 178.788 (171.62) 175.609 (-55.22) -57.205 (86.44) 82.646 (172.92) 176.523 (-55.27) -58.618 (-177.09) 178.903 (173.02) 176.513 (-55.32) -58.597 (-177.20) 178.707 (171.53) 175.681 (-55.07) -57.324 (85.26) 82.4468
Compound 23
N
H
OMs
56
Molecule (-950.28 au) E gas(kcal/mol)
Rel. E gas(kcal/mol)
Conformer.1 -15.594 0Conformer.2 -14.214 1.37975Conformer.3 -13.572 2.022Conformer.4 -11.381 4.21235Conformer.5 -11.316 4.27743Conformer.6 -11.189 4.40471Conformer.7 -11.162 4.43167Conformer.8 -10.834 4.75978Conformer.9 -8.3142 7.27939
minimized conformers
relative energies kcal/mol
Conformer.1 -950.286 0Conformer.2 -950.283 0.003Conformer.3 -950.284 0.002Conformer.4 -950.28 0.006Conformer.5 -950.28 0.006Conformer.6 -950.284 0.002Conformer.7 -950.279 0.007Conformer.8 -950.279 0.007Conformer.9 -950.28 0.006
Dih(C7,S1,O1,C6) Dih(S1,O1,C6,C5) Dih(O1,C6,C5,C4)
(152.36) 155.656 (73.20) 62.176 (177.16) 177.385(-176.13) -165.78 (-79.66) -76.574 (-60.21) -57.037(-177.69) -177.69 (-177.07) -177.07 (-63.44) -63.442(178.61) 178.001 (177.68) 175.028 (-65.56) -61.991(176.29) 174.361 (169.98) 166.989 (-61.49) -61.74(179.93) 163.118 (-177.45) 76.9851 (-65.65) -105.68(-161.08) -167.11 (-80.94) -77.565 (-53.07) -53.012(176.55) 179.243 (-111.25) -96.36 (-63.05) -57.357
57
(178.61) 161.176 (177.68) 79.8869 (-65.58) -99.912
Dih(C6,C5,C4,C3) Dih(C5,C4,C3,C2) Dih(C4,C3,C2,C1)(-175.68) -177.76 (53.05) 52.4185 (-53.15) -52.174(-172.59) -177.07 (53.60) 52.4285 (-53.91) -52.473(-177.53 )-177.53 (52.38) 52.383 (-52.44) -52.442(-74.53) -74.429 (-52.39) -52.206 (53.85) 52.1834(-75.54 )-73.984 (-52.49) -51.91 (54.44) 51.9695
(-173.68) -178.25 (53.65) 53.4138 (-53.73) -52.106(-75.57) -73.957 (-52.81) -52.625 (55.03) 52.5691(-74.75) -74.033 (-52.27) -52.412 (53.84) 52.192(-74.54) -73.727 (-52.38) -51.549 (53.85) 51.7651
Dih(C3,C2,C1,N1) Dih(C2,C1,N1,H2) Dih(C1,N1,H2,C5)(56.22) 55.7384 (176.59) -178.25 (124.31) 120.932(56.18) 55.9175 (177.31) -179.56 (124.98) 121.964(55.77) 55.7664 (179.76) 179.763 (122.66) 122.659(-55.46) -54.586 (-172.23) -179.77 (-131.65) -125.23(-53.51) -54.761 (-173.90) -62.887 (127.50) 122.463(56.02) 55.3488 (176.35) -179.85 (125.54) 121.82(-53.35) -54.513 (-75.89) -63.883 (128.37) 22.828(-55.43) -54.297 (-171.55) -179.43 (-132.33) -125.9(-55.46) -55.398 (-172.23) -177.86 (-131.63) -125.39
Dih(H2,N1,C5,C6) Dih(N1,C5,C6,O1)(-57.32) -60.149 (57.18) 55.092(-57.77) -59.175 (-179.95) -179.55(-58.22) -58.224 (173.78) 173.779(-58.53) -51.197 (170.15) 171.569
(-155.62) -168.32 (171.80) 171.669(-56.20) -58.859 (174.34) 133.087
(-153.39) -166.89 (-179.58) -179.7
58
(-59.40) -52.1 (172.81) 176.51(-58.52) -53.133 (170.13) 135.128
Compound 22
N
H
OCH3
Molecule (-793.00 au)
E gas(kcal/mol)
Rel. E gas(kcal/mol)
Conformer.1 17.5042 0Conformer.2 17.5373 0.03316Conformer.3 17.619 0.11485Conformer.4 17.764 0.25979Conformer.5 18.1486 0.64442Conformer.6 18.1582 0.65398Conformer.7 18.2875 0.78334Conformer.8 18.3287 0.8245Conformer.9 18.3288 0.82465Conformer.10 18.3653 0.8611Conformer.11 18.4925 0.98828Conformer.12 18.6892 1.18497Conformer.13 18.7151 1.21088Conformer.14 18.8014 1.29723Conformer.15 18.8129 1.30868Conformer.16 18.8917 1.38756Conformer.17 18.9328 1.42857Conformer.18 39.0939 21.5897Conformer.19 18.9513 1.44708Conformer.20 18.9358 1.43158Conformer.21 18.9807 1.47647Conformer.22 19.0061 1.50195Conformer.23 19.07 1.5658Conformer.24 19.152 1.64784Conformer.25 19.5415 2.03731Conformer.26 19.6977 2.19354Conformer.27 19.738 2.23378
59
Conformer.28 19.7355 2.23136Conformer.29 19.7627 2.25853Conformer.30 19.8291 2.32495Conformer.31 19.9314 2.42726Conformer.32 20.0021 2.49794Conformer.33 20.169 2.66479Conformer.34 20.2437 2.73955Conformer.35 20.2864 2.78219Conformer.36 20.3622 2.85801Conformer.37 20.3708 2.86664Conformer.38 20.3959 2.89172Conformer.39 20.4211 2.91692Conformer.40 20.5019 2.9977Conformer.41 20.5394 3.0352Conformer.42 20.7003 3.19609Conformer.43 20.7203 3.21608Conformer.44 20.8007 3.29655Conformer.45 20.8251 3.32091Conformer.46 20.8602 3.35601Conformer.47 21.0125 3.50829Conformer.48 21.0421 3.5379Conformer.49 21.0823 3.57814Conformer.50 21.3581 3.85392Conformer.51 21.3722 3.868Conformer.52 21.4028 3.89864Conformer.53 21.4518 3.94763Conformer.54 21.3874 3.88317Conformer.55 21.5361 4.03195Conformer.56 21.882 4.37777Conformer.57 21.9144 4.41017Conformer.58 21.9183 4.41413Conformer.59 22.0517 4.54756Conformer.60 22.0916 4.5874Conformer.61 22.2113 4.70713Conformer.62 22.6133 5.10907Conformer.63 22.6313 5.1271Conformer.64 22.7949 5.29069
60
Conformer.65 22.898 5.39383Conformer.66 22.9307 5.42651Conformer.67 23.2829 5.77876Conformer.68 23.3617 5.85749Conformer.69 23.3886 5.88438Conformer.70 23.459 5.95482Conformer.71 23.4635 5.95933Conformer.72 23.5229 6.01875Conformer.73 23.5775 6.07336Conformer.74 23.6562 6.15205Conformer.75 23.9021 6.39791Conformer.76 24.0368 6.53259Conformer.77 24.1627 6.65856Conformer.78 24.1627 6.65856Conformer.79 24.6672 7.16304Conformer.80 24.7268 7.22266Conformer.81 24.7826 7.27841Conformer.82 24.8439 7.33972Conformer.83 24.8442 7.34001Conformer.84 24.8602 7.35603Conformer.85 25.0723 7.56813Conformer.86 25.3606 7.85638Conformer.87 25.3712 7.867Conformer.88 25.7767 8.2725Conformer.89 25.8797 8.37551Conformer.90 25.9326 8.42844Conformer.91 26.3208 8.81664Conformer.92 26.3963 8.89214Conformer.93 26.7663 9.26206Conformer.94 26.8089 9.30476Conformer.95 26.8301 9.32593Conformer.96 26.8692 9.36498Conformer.97 26.8904 9.38626Conformer.98 27.0051 9.50089Conformer.99 27.0081 9.50395Conformer.100 27.1492 9.64506
61
minimized conformers relative energies kcal/mol
Conformer.1 -793.4567 0.0002 Conformer.2 -793.4569 0 Conformer.3 -793.4554 0.0015 Conformer.4 -793.4550 0.0019 Conformer.5 -793.4552 0.0017 Conformer.6 -793.4527 0.0042
Dih(C17,C16,C15,C14)
Dih(C16,C15,C14,C13)
Dih(C15,C14,C13,C12)
Dih(C14,C13,C12,C11
(-179.89) 180 (179.82) -180 (-179.78) -180 (179.73) 180(-179.95) -65.555 (-179.52) -177.44 (-179.98) 179.079 (-179.29) -177.27
(-179.98) -180 (-179.91) 180 (-179.98) -180 (-179.88) 180(179.97) 64.963 (179.99) 172.969 (179.95) 178.408 (179.95) -178.2(65.61) 179.999 (175.85) -180 (179.80) 179.998 (179.64) -179.98
(-179.03) 175.670 (-175.53) 60.470 (-175.18) 55.928 (-56.86) 60.3974
Dih(C13,C12,C11,C10) Dih(C12,C11,C10,C9) Dih(C11,C10,C9,C8) Dih(C10,C9,C8,C7)(-179.75) -180 (179.81) 180 (-179.78) -180 (179.94) 179.996
(179.93) -58.442 (-179.49) -60.79 (179.78) -178.87 (-179.54) -62.14(179.98) -180 (179.42) 179.997 (174.89) 179.992 (61.68) -178.65
(179.83) -58.268 (179.65) -61.925 (175.05) 177.862 (66.19)
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